Congenital myopathies describes a set of genetic diseases that predominantly affect the muscles. The first report of a congenital myopathy was of a patient with central core disease (CCD) in 1956. Since that time, the classification of congenital myopathy has been evolving from a primary pathologic diagnosis to one with a genetic basis.
The typical features of congenital myopathy include early-onset muscle weakness, often associated with features of low muscle bulk and tone. While these features are typically found in neonates and infants, children or even adults can present with milder forms of congenital myopathy. In certain cases, patients can have normal strength and tone but be at risk of rhabdomyolysis and/or malignant hyperthermia. Due to the early weakness, dysmorphic features such as contractures, a high arched palate, and facial dysmorphisms can be seen.
The classification of congenital myopathies has evolved to no longer be a pure pathologic diagnosis but rather relying more on genetic data. However, the genotype-to-phenotype correlation is variable on the gene level and more accurate when described by a specific mutation. Given this, the taxonomy of congenital myopathies can be somewhat confusing. Diagnosis should be a combination of genetic, phenotypic, and, if needed to confirm, pathologic, electrodiagnostic, and serum features.
The skeletal muscle involvement can also result in secondary breathing and swallowing difficulties. However, non-skeletal muscle features can manifest based upon the specific disease.
Additionally confounding is that, more recently, genes known to cause congenital myopathy have now also been described to cause a dystrophic process such as seen in congenital muscular dystrophies. However, the traditional pathologic subdivision of congenital myopathy does give some guidance in regards to genotype and prognostication and cannot be disregarded. As such, the congenital myopathies can be divided into 6 pathologic categories.[1, 2]
nemaline myopathy (subtypes: rod, core-rod, cap and zebra body myopathy);
core myopathy (subtypes: central core and multiminicore myopathy);
centronuclear myopathy (subtypes: myotubular myopathy and autosomal centronuclear myopathy);
The gene affected in each disease predicts the presentation of disease features. However, amongst each gene there are variations in presentation based upon the specific change. Occasionally, these result in phenotypic overlap between genes as well as genes causing congenital myopathy to occasionally have phenotypes more consistent with congenital muscular dystrophies, limb-girdle muscular dystrophies, or even possible neuropathic or neuromuscular junction diseases.
Additionally, each gene may have other tissue expression, which can result in non-muscle symptoms.
The true incidence of congenital myopathies is unknown as no large population-based studies have been conducted. However, there are a varied number of stuidies that demonstrate a relative incidence of the diseases. Of hypotonic infants due to neurologic causes, approximately 60%–80% were from a central cause and 12%–34% were from a peripheral cause.[3, 4] In the children with a peripheral cause of hypotonia, less than 50% of the cases were due to congenital myopathy.[3, 4]
The frequency of symptom onset was in the neonatal period in 76% of cases in one cohort study.[5]
Mortality/Morbidity
Given the wide spectrum of disease, the largest cause of morbidity and mortality is related to muscle function loss resulting in respiratory and/or feeding failure.
According to the study by Colombo et al., at birth, neonates with congenital myopathy required respiratory support and nasogastric feeding in 30.4% and 25.2% of cases, respectively. Of note, in the study cohort 12% of patients died within the first year, whereas 74.1% achieved independent ambulation with 62.9% being late walkers.[5]
Phenotype can vary greatly even in a single gene or pathologic classification. As such, consideration for the specific etiology is needed. Additionally, many infants/neonates with congenital myopathy can make improvements in the first few years of life. This makes early decisions regarding long-term goals of care, such as use of supportive care, difficult.
However, after this initial gain, a small group can decline. The Colombo et al. cohort demonstrated this in the 9% of patients who were ambulatory but lost the ability.[5] While this can be from the primary pathologic process, this may also be related to a relative weakness in the context of a growing child with disproportionate needs for strength as compared to what their muscles can produce and may not be objective worsening weakness.
Other morbidities include extra-muscular features or risks. Most noticeably is the risk for malignant hyperthermia. While this is best described in a subset of patients with RYR1 mutations, there are other myopathic and dystrophic genes that can also be causative. There are also non-myopathic phenotypes of these genes that can have non-weak presentations.
Sex
Any sex bias is dictated by the underlying genetic mutation. Given most diseases are autosomal, the most common form of variance is in the form of CNM1, which causes x-linked myotubular myopathy.
Age
The classic age of presentation is in the neonatal period, but milder forms can present at any age.
The prognosis for congenital myopathies varies broadly. In the most severe cases newborns and infants may die, while milder mutations result only in mild weakness and some effects on activities of daily living (ADL).
History will vary based upon the underlying genotype. Additionally, while there is some predictive value of the history, with emerging mutations being described, there are atypical cases and a broader consideration is sometimes needed to differentiate.
Most congenital myopathies present in childhood with a significant majority presenting in infants or neonates. The hallmark feature, given skeletal muscle involvement, is weakness. However, this weakness also presents with respiratory and/or feeding difficulties. Other features can differentiate the subtypes of congenital myopathy with either the pattern of muscle weakness or extra-muscle involvement. In late-onset disease, upon detailed questioning, often a history of infantile hypotonia and/or delayed motor milestones can be revealed.
In cases of autosomal dominant or x-linked disease, a family history can be indicative of cause.
Below, the subtypes described in the introduction are further differentiated. These include examples and are not meant to be all inclusive of an ever-expanding list.
Nemaline (rod) myopathy can be caused by mutations in at least 10 different genes. Of the mutations described, all but one (KBTBD13) is a component or interacts with muscle thin filament. Mutations likely impair the proper formation, maintenance, or function of thin filaments, which results in accumulation of sarcomeric components and formation of nemaline bodies (rods) and associated muscle weakness.
General features of all nemaline myopathies include minimally progressive or nonprogressive proximal limb, bulbar, and facial weakness starting in the neonatal or childhood periods. Additionally, often people present with hypotonia and respiratory insufficiency, which is the most common cause of death.
Skeletal deformities range from arthrogryposis in the severe congenital form to limb contractures, kyphoscoliosis, pectus excavatum, and rigid spine. Cardiomyopathy is rare but can be present early with congenital presentation, or it can be a late complication in childhood-onset or adult-onset cases. CNS disease is rare, but seizures have been reported in severe cases in the neonatal period.
The most common type of nemaline rod myopathy presents in the infantile stage with 42% of patients presenting in the neonatal period.[6] While there has been an association with polyhydramnios, decreased fetal movements, and an abnormal fetal presentation or fetal distress, these features were only involved in half or less of patients.[6]
Nemaline myopathy 1 (NEM1)
NEM1 is due to a mutation in the gene for α-tropomyosin 3 (TPM3). This is likely a rare cause (< 3%) of nemaline myopathy, but variants in TPM3 can also cause a congenital fiber-type disproportion myopathy subytpe.[7] Tropomyosins are a family of actin-binding coiled-coil proteins that help to regulate calcium-dependent muscle contraction. Multiple isoforms exist, with three striated muscle isoforms: α-tropomyosinfast (TPM1), β-tropomyosin (TPM2), and α-tropomyosinslow (TPM3). In muscle, the heterodimers α-tropomyosinslow–β-tropomyosin (slow twitch) and α-tropomyosinfast–β-tropomyosin (fast twitch) are most common.
In human and animal studies of a dominant mutation of TPM3, a number of functional defects were noted. There was reduced affinity for F-actin, reduced formation of preferred α/β heterodimers in favor of α/α heterodimers, destabilization of the coiled coil, impaired binding to tropomodulin, and reduced sensitivity of isometric force production to activating calcium.[8, 9, 10]
Autosomal dominant inheritance is usually due to a missense mutation and causes a moderate phenotype with onset between birth and 15 years of age. Weakness is diffuse and symmetric with slow progression often with need for a wheelchair in adulthood. Respiratory failure is common. Other features include kyphoscoliosis and a thin body habitus.
Autosomal recessive inheritance is usually due to a nonsense mutation causing a stop codon. Onset is at birth with moderate-to-severe hypotonia and diffuse weakness. In the most severe cases, death can occur before 2 years of age. Less severe cases have delayed major motor milestones, and these patients may walk, but often need a wheelchair before 10 years of age.
In autosomal recessive cases in which no functional α-tropomyosin is present, altered ratios of the remaining sarcomeric proteins may be sufficient to cause the formation of rods.
Nemaline myopathy 2 (NEM2)
NEM2 is due to a mutation in the gene for nebulin (NEB) and is likely the most common cause of nemaline myopathy. Nebulin is a large protein that extends the whole length of the thin filament. It has a highly repetitive structure (repeats have an α-helical structure) and can bind up to 200 actin molecules. This protein is present in skeletal and cardiac muscle. It is required for the proper assembly of thin filaments and for the maintenance of thin filament length and contractile function. Additionally, it is also likely responsible for proper periodicity of the troponin/tropomyosin complex. Multiple isoforms exist, differing in the C-terminal structure, which binds α-actinin in the Z-disk, and nebulin likely plays a role in Z-disk assembly.
Small deletions and duplications causing frameshifts and point mutations causing stop signals or altered splicing are more common than missense mutations.[11] No mutational hotspots exist. It is expected that nonsense and frameshift mutations cause mRNA instability or truncated nebulin molecules ,while missense mutations likely disrupt the binding of actin to nebulin or affect the secondary structure of nebulin.
A clear genotype-phenotype correlation does not exist, but, in milder disease, it is likely that several normal isoforms are expressed.
Inheritance in all cases has been autosomal recessive with very variable phenotypes,[12] with all but the adult-onset form being described in a large series encompassing 55 families.[11]
The severe congenital form presents at birth with severe hypotonia and weakness. Lack of movement, poor suck and swallow, and respiratory failure are frequent findings. Death in utero due to fetal akinesia has been described. Arthrogryposis and severe respiratory failure are associated with early death that usually occurs within the first 2 years of life.
The intermediate congenital form presents with weakness in early childhood and is characterized by delayed motor milestones and contractures. Children with this form usually need a wheelchair or ventilatory support by age 10 years.
The typical (most common) congenital form presents within the first year of life with hypotonia, generalized limb weakness, facial weakness, feeding difficulty, and mild respiratory weakness. Features such as elongated face, tent-shaped mouth, high arched palate, and retrognathia are common. Progression is static or very slow, and, after an initial rocky course, stabilization leads to an independent life.
The childhood-onset form presents with distal leg weakness in the late first or early second decade. Proximal muscles are involved later, and wheelchair dependency occurs in midlife.
The adult-onset form presents with symmetric proximal weakness in persons aged 20–50 years. Other features may include neck extensor weakness, respiratory insufficiency, or rapid progression.
Other forms include patients who do not fit any of the above presentations and can have cardiomyopathy, ophthalmoplegia, or an unusual distribution of weakness.
Nemaline myopathy 3 (NEM3)
NEM3 is due to autosomal dominant, autosomal recessive, or sporadic de novo mutations in alpha-actin (ACTA1). It is likely the second most common cause of nemaline myopathy (20%–30%), and overrepresents the severe phenotype. Alpha-actin is present in skeletal muscle but not cardiac muscle. Overall, this protein makes up 10%–20% of all muscle protein.[13] The actin monomer, G-actin (has binding site for myosin) polymerizes to form F-actin. Two strands of F-actin combine in a double helix as part of the thin filament. F-actin binds to other thin filament proteins including nebulin, tropomyosins, and troponins and most importantly binds myosin during muscle contraction.
Most mutations are missense and spread throughout the gene. Autosomal dominant mutations exert a dominant negative effect and autosomal recessive mutations that result in no functional actin both cause cytoplasmic rods, suggesting that multiple mechanisms are responsible for disease manifestations. ACTA1 mutations may have one or more effects: increase or decrease of 1) polymerization into F-actin, 2) the sliding speed of actin filaments, 3) calcium regulation, or 4) the strength of binding to α-actinin.[14]
In autosomal dominant disease, there are likely abnormalities in folding, polymerization, or aggregation of mutant actin, whereas in autosomal recessive disease, altered ratios of sarcomeric proteins during development or turnover of the thin filament are sufficient to form rods. Therefore, nemaline rods may result from either changes in normal stoichiometry of sarcomeric proteins or due to the presence of mutant α-actinin.
The degree of sarcomeric disruption, as seen on electron microscopy, correlates with disease severity such that, in general, the most severely affected patients have the most myofibrillar disorganization.
Autosomal dominant cases are usually mild, and recessive cases are usually severe. In a large series of 109 patients with nemaline myopathy 26% had a mutation in ACTA1.[15] More than 50% of patients had the severe congenital form of nemaline myopathy, although rare adult-onset cases have been described.
In a large series reporting previously published reports and unpublished data from the authors,[14] 177 different mutations were described, 157 being missense and 133 being de novo. Mutations occurred in 29% of the amino acid residues throughout α-actin.
Mutations in ACTA1 can also cause nemaline myopathy with intranuclear rods.15 Cases are most often sporadic but can be autosomal dominant. Presentation is likely similar to the typical nemaline myopathy, with 43% of cases having a severe congenital form, although adult-onset cases have been described. Other diseases described due to ACTA1 mutations include (1) actin filament aggregate myopathy[16] usually causing severe disease, (2) myopathy with core-like areas[17] , and (3) congenital fiber type disproportion (see below).
Nemaline myopathy 4 (NEM4)
NEM4 is due to an autosomal dominant mutation in the gene for β-tropomyosin (TPM2). It is a rare cause of nemaline myopathy. Abnormal tropomyosin-actin interactions resulting in reduction in force generation, increased activation of myosin ATPase, and destabilization of the coiled-coil structure have been reported.
Mutations have also been associated with distal arthrogryposis and pterygia suggesting that β-tropomyosin may have a unique role during fetal development, particularly in distal muscles.
Presentation is from infancy to childhood with hypotonia and moderate-to-severe proximal weakness with minimal or no progression. Major motor milestones are delayed, but independent ambulation is usually achieved, although a wheelchair may be needed in later life.
Other problems can include feeding difficulties as an infant, facial weakness, long narrow face, high arched palate, kyphoscoliosis, and respiratory failure.
One consanguineous family with autosomal recessive inheritance has been described with a TPM2 mutation and Escobar syndrome[18] (thick skin folds keeping joints in a fixed position). Presentation was at birth with hypotonia, pterygia, and arthrogryposis.
A mutation in TPM2 has also been described in cap myopathy.[19] This disease has only been described in 5 sporadic cases and in one family with dominant inheritance. Presentation is either congenital or childhood onset of hypotonia with facial and slowly progressive proximal weakness. Respiratory failure may result in death in teenage years. Other features include a long narrow face and scoliosis. About 50% of muscle fibers showed a crescent-shaped peripheral cap that was granular in appearance on the modified GT stain and reacted strongly to NADH, phosphorylase, and periodic acid-Schiff, but not to myosin ATPase. On electron microscopy (EM), the caps were filled with abnormally arranged myofibrils, which lacked thick filaments.
Distal arthrogryposis has also been described as due to a mutation in TPM2.20 Presentation is at birth with flexion contractures of hands and feet.
Nemaline myopathy 5 (NEM5)
NEM5 is due to an autosomal recessive mutation in the gene for troponin T1 (TNNT1) and has been described only in the Old Order Amish.[20] The mutation causes a premature stop codon. The truncated protein removes the principal site of binding to troponin C and troponin I. It is hypothesized that the mutation results in mutant message undergoing nonsense-mediated decay or an unstable protein that is degraded. There is therfore a complete loss of troponin T1. Early compensation at birth may be due to fetal transcription of TNNT2 and TNNT3.[21]
Onset is during the first few months of life with hypotonia, proximal weakness as well as jaw and limb tremors that resolve over a few months. Death occurs before age 2 years from respiratory failure. Other features include shoulder and hip contractures and pectus carinatum.
Nemaline myopathy 6 (NEM6)
NEM6 is due to an autosomal mutation in Kelch repeat and BTB/POZ domains-containing protein 13 (KBTBD13).[22] KBTBD13 protein localizes to the cytoplasm of skeletal and cardiac muscle. More than 60 proteins of the BTB/Ketch family have been identified. Functions include cytoskeletal modulation, regulation of gene transcription, ubiquitination, cell migration, and myofibril assembly.[22] Pathologic changes in muscle biopsies include numerous rods near Z-disks, type 1 fiber predominance and hypertrophy, and unstructured cores devoid of oxidative enzyme activity.[22]
Presentation is in childhood with the inability to run or jump with slow progression of the disease. Often, movements are slow with significant proximal neck and shoulder weakness.[22]
Nemaline myopathy 7 (NEM7)
NEM7 is due to an autosomal recessive mutation in the gene for cofilin-2 (CFL2) and has been described in one family.[23] Cofilins are actin-modulating proteins that act to depolymerize F-actin and inhibit the polymerization of G-actin. Cofilin-2 is a muscle-specific isoform that exerts its effect on actin, in part, through interactions with tropomyosin.
The patients presented at birth with hypotonia and generalized weakness. Major motor milestones are delayed, but independent ambulation is achieved.
Nemaline myopathy 8 (NEM8)
NEM8 is due to an autosomal recessive mutation in the gene for Kelch-like family member 40 (KLHL40).[24] This is a common form of severe nemaline rod myopathy, accounting for 20% of all cases screened and 28% of patients in the Japanese population[24] . KLHL40 is a member of the Kelch-repeat-containing protein superfamily. Members of this family have a wide range of functions, which generally involve protein-protein interactions. KLHL40 is more abundant in fetal skeletal muscle than in adult muscle and localizes to the A-band. Muscle pathology from affected patients showed numerous small rods, many requiring EM for visualization. KLHL40 immunostaining is reduced or absent in muscle of patients harboring a mutation. Knockdown of KLHL40 in Zebrafish resulted in disruption of myofibers, widened Z-disks, aggregates containing a-actinin (Z-disk protein), and loss of movement. It is thought to likely play a role in muscle development and function.[24]
Patients present at birth with severe symptoms. The majority have fetal akinesia or hypokinesia. Respiratory failure, facial weakness, facial dysmorphism, dysphagia, contractures, and diffuse weakness occur in more than 90%. In one series, ventilation was needed in 38% and gastrostomy tube was needed in 54%. Other features included ophthalmoparesis and pathological fractures. Overall, many patients died within the first 6 months of birth, although some lived into the second decade.[24]
Nemaline myopathy 9 (NEM9)
An autosomal recessive mutation in Kelch-like family member 41 (KLHL41) can cause nemaline rod myopathy type 9.[25] A severe phenotype due to a frameshift mutation presents with decreased fetal movements, breech presentation, arthrogryposis, and skeletal abnormalities. Death was before 3 months of age. In contrast, missense mutations result in mild to moderate weakness, contractures, and mild skeletal deformities with life into teenage years. Wheelchair and respiratory support are needed in some, but other patients remained ambulatory without assistive devices.[25]
Muscle pathology showed sarcoplasmic rods, EM evidence of severe myofibrillar disarray, and KLHL41 reduction or absence by immunostaining. Knockdown of KLHL41 diminished motor function, nemaline bodies, and myofibrillar disorganization.[25]
Nemaline myopthay 10 (NEM10)
NEM10 is due to mutations in leiomodin-3 (LMOD3) gene in a recessive fashion. Like many of the other subtypes, there is a severe phenotype with respiratory insufficiency, severe weakness, and feeding difficulties, but no cardiac abnormalities. In this subtype, death during the neonatal period has been described.[26] However, a milder subtype has also been described with marked facial weakness but retained ambulation in 3 of 4 patients.[27]
Pathology
Rods, the pathologic hallmark of nemaline rod myopathy, are only visible on modified Gomori trichrome (GT) stain as dark red/purple structures (see image below).
View Image
Nemaline rod myopathy, Gomori trichrome (GT) stain. Dark blue structures are seen only with this stain. They contain Z disk material, including alpha-....
Usually, the rods are sarcolemmal but may be intranuclear.
Derived from the Z-disk, rods are often in continuity with the Z-line. They are composed of primarily α-actinin (the primary component of Z-lines) as well as other Z-line and thin filament proteins, including actin, telethonin, and myotilin. Rods presumably form secondary to contractile protein (especially thin filament) dysfunction.
Rods may be seen in many other diseases including inflammatory myopathies, muscular dystrophies, mitochondrial myopathies, HIV myopathy, chronic renal failure, spinal muscular atrophy, Charcot-Marie-Tooth disease, and monoclonal gammopathy.
Other common pathologic features include type-1 fiber predominance or atrophy.
Central core disease (CCD) is due to either autosomal dominant or recessive mutations in the ryanodine receptor (RYR1) gene.
The typical presentation of this congenital myopathy is in an autosomal dominant fashion with onset at birth or early childhood. Typically, patients present with nonprogressive limb weakness, mild facial weakness, and hypotonia. As with other congenital myopathy, hypotonia, arthrogryposis, and a history of decreased fetal movements can be common.
However, more severe forms can present with neonatal akinesia syndromes and severe respiratory distress and feeding difficulties after birth. On the other end of the spectrum, a late-onset, slowly progressive limb-girdle-type disease, or even malignant hyperthermia in an otherwise asymptomatic patient, have been known presentations.
CCD is usually transmitted in an autosomal dominant fashion with variable expression and incomplete penetrance (rare autosomal recessive and sporadic cases) and is almost always due to a mutation in the ryanodine receptor 1 (RYR1). CCD has been reported in a few families with familial hypertrophic cardiomyopathy due to a mutation in the cardiac myosin b-heavy chain.
Mutations (most often missense) in RYR1 can cause CCD, as described above, malignant hyperthermia susceptibility, or both. Mutations in RYR1 can also cause core-rod myopathy, multiminicore myopathy, and rare cases of centronuclear myopathy.
RYR1 is the calcium channel on the sarcoplasmic reticulum (SR) that releases calcium into the muscle cytoplasm during excitation-contraction coupling, thereby allowing calcium to interact with muscle contractile proteins. It exists as a tetrameric structure and associates with several other proteins including the dihydropteridine receptor, calmodulin, and calsequestrin. Ordered two-dimensional arrays are formed at the junctional terminal cisternae, in which each of the 4 subunits in every other RYR1 tetramer is physically coupled to a dihydropteridine receptor, and each RYR1 tetramer is physically coupled to 4 other tetramers.
One hypothesis proposed to explain malignant hyperthermia suggests that it results from abnormal repetitive Ca2+ cycling, characterized by spontaneous Ca2+ release and reuptake triggered by volatile anesthetics, stress, or elevated temperature.[28]
The basis for this hypothesis is that RyR1 mutations cause a lowered threshold for store overload-induced Ca2+ release (SOICR). SOICR is the process by which there is a rapid release of Ca2+ store when the size of the Ca2+ store reaches a certain threshold triggered by luminal Ca2+ concentration. (This sensor mechanism is in addition to a cytosolic Ca2+ sensor).
Halothane further lowers the mutation-lowered SOICR threshold causing RYR1 to be triggered to open when the free luminal Ca2+ level overshoots its lowered SOICR threshold. Elevated cytosolic Ca2+ then triggers muscle contraction and hypermetabolism.
Other proposed mechanisms for malignant hyperthermia include inter-domain unzipping of RYR subunits, changes in RYR redox status, increased rate of Ca2+ entry into the sarcoplasmic reticulum lumen following adrenergic stimulus, changes in RyR phosphorylation status and elevated enzymatic Ryr function.
A hypothesis to explain phenotypic variability, variable penetrance and core formation is based on nonuniformity of the Ca2+ release unit48 The Ca2+ release unit refers to the two-dimensional array of RyR1 molecules described above.
Because CCD is typically associated with heterozygous missense mutations, both wild type and mutant subunits are expressed. Random combination of subunits into RyR1 tetramers would produce 16 possible arrangements with 6 variants (homotetrameric wild type channels [1], homotetrameric mutant channels [1] and heterotetrameric channels in arrangements 3:1 [4]; 1:3 [4], 2:2 (side by side-[4]); 2:2 (diagonal-[2]).
The random association of different subunits within each tetramer followed by the random association of the 16 different types of tetramers within each Ca2+ release unit would set the stage for nonuniformity of Ca2+ release. This could also lead to nonuniformity of contraction among sarcomeric domains and subsequently to nonuniformity within myofibrils, myofibers, and muscle fasciculi ultimately, resulting in variable degrees of weakness that characterize RyR1-related myopathies.
Cores could be formed due to discordant contraction between adjacent myofibers. This would cause physical stress that could lead to tearing and shearing between myofibrils as well as displacement of mitochondria and the sarcotubular system. Eventually, small foci of damage would coalesce and manifest as cores.
Malignant hyperthermia
About 70% of patients with malignant hyperthermia have a mutation in the RYR1 gene.[29] Malignant hyperthermia susceptibility 1 (MHS1) locus is the RYR1 gene. King-Denborough syndrome is included at this locus. Presentation is in childhood or adolescence usually with malignant hyperthermia. Non-progressive mild proximal weakness may be present. Mild dysmorphic facies and skeletal abnormalities such as short stature, pectus carinatum/excavatum, and scoliosis or kyphosis are often present. (See Complications for more information.)
Minimally or asymptomatic hyperCKemia
Presentation is usually as an adult with myalgia or fatigue. Malignant hyperthermia may occur.
Multiminicore disease
Multiminicore disease is most commonly autosomal recessive. There are two main genes involved, RYR1 and the selenoprotein N gene (SEPN1), but there are others that have been associated. Mutations in RYR1, while they can cause a central core disease as noted above, can also result in multiminicore, but the exact mechanism to differentiate why they have different causes is unknown. Potential defects may be related to instability of the RYR1 macromolecular complex or to a reduction in the number of RYR1 receptors on the sarcoplasmic reticulum.[30]
In mutations in the SEPN1, the gene can present as a congenital myopathy but can also have a phenotype more consistent with a congenital muscular dystrophy. The role of selenoprotein N in causing multiminicore disease is unknown, but its expression is developmentally regulated in muscle. More than 20 mutations have been described, with more than half resulting in a truncated protein that is likely degraded. Selenoprotein N may play a role in redox reactions of membrane proteins, including the ryanodine receptor, and lack of this protein may result in oxidative stress leading to abnormal receptor function.[30] In multiminicore disease due to a mutation in the Selenocysteine insertion sequence-binding protein 2 (SECISBP2) gene, the reduced synthesis of all selenoproteins including selenoprotein N likely accounts for the similar pathology.[31]
How mutations in the rare causes of multiminicore disease result in similar muscle pathology is unknown.
The classic and most common phenotype presents with spinal rigidity, axial weakness, scoliosis, and early respiratory impairment. In this type, the onset occurs in infancy or early childhood and is characterized by proximal and axial weakness and hypotonia that is either nonprogressive or only minimally progressive. There is often associated facial and bulbar weakness. The progressive respiratory weakness is often out of proportion to the muscle weakness. This results in ambulant patients requiring ventilatory support in some cases. There is typically normal intelligence and no clear association with malignant hypertheramia but there are some cases of older patients associated.[32]
As with other congenital myopathies, arthrogryposis can be associated with early-onset symptoms. In patients with RYR1 myopathy, central core type phenotypes exist with the multiminicore pathologic features.
The pathologic hallmark of the disease is the presence of multiple areas of sarcomeric disorganization associated with diminished mitochondrial oxidative activity.
The disease is best identified with muscle reacted for oxidative enzymes NADH, SDH, and COX. Reduced staining for myosin ATPase, glycogen, and phosphorylase may also be noted.
Multiminicores differ from central cores in the following ways: occur in type 1 and type 2 fibers; poorly defined limits; vary in orientation to muscle fiber axis; multiple lesions within one muscle fiber; and smaller in size, never extending the length of the muscle fiber.
Other features may include increased endomysial connective tissue, increased internal nuclei, and type-1 muscle fiber predominance.
Multiminicores may be present as a nonspecific feature in many other diseases, including mitochondrial diseases, CNS disorders, and denervation.
Rare causes of muscle pathology showing multicores or minicores include the following:
Mutations in SECISBP2 lead to multisystem selenoprotein deficiency including in SEPN1.[31] Patients have a multisystem disorder including early onset of axial and proximal muscle weakness, stiff spine, respiratory difficulty, and fatigue. Other features include developmental delay, azoospermia, cutaneous photosensitivity, Raynaud’s, hearing loss, impaired T-lymphocyte proliferation abnormal mononuclear dell cytokine secretion, and telomere shortening.
SCAD (Short-chain acyl-CoA dehydrogenase) deficiency;[33] neonatal onset patients had hypotonia, developmental delay, speech delay, myopathy, lethargy, and feeding difficulties. Later onset patients had ophthalmoplegia, ptosis, weakness and scoliosis.
EMARDD (early-onset myopathy with areflexia, respiratory distress and dysphagia) due to a mutation in multiple epidermal growth factor-like domains 10 (MEGF10);[34] presentation before 1 year with severe proximal and distal weakness, hypotonia, respiratory impairment, scoliosis and joint contractures with stabilization in teenage years.
Titin (LGMD2J) gene mutation was reported to cause a minicore-like disease with early-onset myopathy and fatal cardiomyopathy in 2 consanguineous families.[35] Presentation was before 1 year of age with symmetric proximal, distal and facial weakness, ptosis, joint and neck contractures, spinal rigidity, and progressive dilated cardiomyopathy with concomitant ventricular rhythm disturbances and sudden cardiac death.
Myosin – Cardiac b heavy chain (MYH7) mutations most often cause myosin storage myopathy/hyaline body myopathy (see below), but a variant syndrome causes multi-minicore disease with variable cardiac involvement.[36] Presentation is in childhood with slowly progressive weakness, proximal or distal, facial weakness, scapular winging, contractures, spinal rigidity and variable degrees of cardiorespiratory impairment later in life. Sudden cardiac death may occur.
The centronuclear myopathies (CNM) can be divided into three categories based upon their inheritance pattern: (1) X-linked form, (2) autosomal recessive form, and (3) autosomal dominant form. Nomenclature is sometimes confusing given the numbering system is based upon recognition of the pathology and not on the inheritance pattern.
Autosomal dominant forms
CNM1
CNM1 is caused by mutations in the dynamin 2 gene (DNM2).[37, 38] Dynamins are large GTPases that are involved in organelle fission events. Dynamin 2 has been implicated in endocytosis, and a likely hypothesis is that endocytotic function is disrupted due to mutations in dynamin 2. Other actions of dynamin that may play a role in disease pathogenesis include actin assembly, cytokinesis, and regulation of centrosomal function. Dynamin 2 mutations can also cause a CMT 2 phenotype with axonal neuropathy and clinical features that overlap with autosomal dominant centronuclear myopathy.
The mutations in DNM2 account for about 50% of cases but only 15% of pediatric cases.[39, 40] Most patients have a mild phenotype with onset in adolescence or adulthood with axial/neck flexor as well as distal more than proximal limb weakness and slow progression. Other features can include facial weakness, ptosis, ophthalmoplegia, and contractures, especially of the ankles.
However, a more severe phenotype has been described at birth with hypotonia and a poor suck. There is often also facial weakness, high-arched palate, ptosis, ophthalmoplegia, joint hyperlaxity, and contractures.
One remarkable factor is that weakness is distal more than proximal, resulting in delayed major motor milestones, but ambulation is usually obtained and there is often slow improvement to young adulthood. Intermediate cases have also been described.[41]
CNM3
CNM3 is caused by mutations in myogenic factor 6 (MYF6). MYF6 appears to be involved in terminal differentiation of myotubes. One family is reported with mild proximal weakness, muscle cramps and elevated CK in the proband. The father also harbored a mutation in dystrophin gene typically causing a mild to moderate phenotype, but had a severe phenotype, presumably due to modification by the MYF6 mutation.[42]
CNM4
CNM4 is caused by mutations in the coiled-coil domain containing protein 78 (CCDC78). CCDC78 is expressed in skeletal muscle, enriched in the perinuclear region and triad, and found in intracellular aggregates in the affected patient’s muscle. Muscle biopsy showed a high proportion of central nuclei, type-1 fiber predominance, desmin positive aggregates, and core-like areas.
This subtype is described in one family. There was neonatal hypotonia, distal more than proximal weakness, excessive fatigue, myalgias, mild to moderate motor impairment with preserve ambulation, and mild cognitive involvement.[43]
Autosomal recessive forms
CNM2
CNM2 is caused by amphiphysin 2 (bridging integrator 1; BIN1). Amphiphysins are involved in endocytosis, signal transduction, transcriptional regulation, and vesicle fusion. Amphiphysin 2 mutations have been shown to impair T-tubule function, formation, or maintenance. BIN1 protein binds to DNM2 protein and mutations in BIN1 may disrupt this binding or binding to T-tubules.
This centronuclear myopathy typically presents at birth but can present in childhood as well. In addition to weakness, there can be contractures, dilated cardiomyopathy, and intellectual disability. The course is slowly progressive, with more than 50% of patients surviving childhood.[44]
CNM5, CNM6, and CNM (RYR1)
SPEG, ZAK, and RYR1 cause the above subtypes of autosomal recessive centronuclear myopathy. Their presentations are similar to the other neonatal-onset centronuclear myopathies and will not be described further.
CNM from titin
Mutations in titin can cause a wide variety of phenotypes.[45] There are cases presenting from birth to 3 years of age with decreased fetal movements, hypotonia, weakness, and respiratory difficulty. Patients typically have more proximal muscle weakness, but there is wide variety of functionality. In most patients there is facial weakness[45] , and in some patients cardiac involvement.[46]
Titin has also been associated with limb-girdle muscular dystrophy type 2J.
X-linked recessive form
CNMX
CNMX is due to mutations in myotubularin (MTM1).[47] Point mutations (missense, nonsense, and splice site), as well as small or large insertions and deletions, have been found throughout the gene. A clear genotype-phenotype correlation does not exist, but most nonsense and splice site, as well as some missense mutations in conserved residues, result in a severe phenotype, and many missense mutations or deletions have a mild phenotype. Myotubularin is ubiquitously expressed in the nucleus of most cells.
Myotubularin is a lipid phosphatase whose main action is to dephosphorylate phosphoinositide-3-phosphate. Phosphoinositides are specialized lipids that target localization of proteins to various subcellular organelles and are important in membrane trafficking.
Myotubularin interacts with proteins with the SET domain that are important in epigenetic mechanisms of gene regulation. Myotubularin may serve as a link between genetic regulatory proteins and signaling pathways involved in vesicular trafficking of substrate necessary for myoblast fusion.
In myotubularin knockout mice, muscle development occurs normally, but a myopathy develops suggesting that the absence of myotubularin affects muscle maintenance, not muscle formation.
In the pediatric population, mutations in MTM1 account for about 50% of CNM cases. Affected males often present in utero with with decreased fetal movements and polyhydramnios. At birth, severe weakness and hypotonia, feeding difficulty, and respiratory distress are present.
There is often noticeable ptosis, facial weakness, and ophthalmoplegia. Skeletal features include pectus carinatum, micrognathia, knee and hip contractures, elongated birth length, narrow face, slender/long digits, and macrocephaly.
Systemically, these boys may have cryptorchidism, pyloric stenosis, gallstones, hepatic dysfunction, spherocytosis, renal calcinosis, and bleeding diathesis.
Currently, the prognosis is poor with 54%–65% of patients dying before 18 months of age.[48, 49] Additionally, 90% required ventilatory support at birth. Fifty-seven percent of survivors older than 1 year need 24-hour ventilator support[50] ; however, these survivors have nonprogressive weakness and can live into adulthood. However, at the time of writing this article, there is a current viral vector-based gene replacement therapy in clinical trials.
Of note, most carriers are asymptomatic, but mild facial and limb weakness may be present. Progression may result in gait difficulty and kyphoscoliosis. Skewed X-inactivation may result in a carrier who presents severely with infant-onset weakness, feeding difficulty, and skeletal deformities.
Pathology
The pathologic hallmark of all myotubular myopathies (X-linked and autosomal) is the predominance of type-1 fibers with large, centrally placed nuclei, as shown below. Centronuclear/myotubular myopathy can be due to several different mutations, but all affected proteins have a role in membrane trafficking or in the maintenance of skeletal muscle fiber orignization, especially in the postitioning of nuclei.[51]
However, it is not known how any of the above mutations cause the pathologic abnormality. In DNM2 -related centronuclear myopathy the additional finding of radiating sarcoplasmic strands from the central nuclei is often present, often best seen on NADH staining.[52]
Most fibers are small and round and resemble fetal myotubes, which normally have central nuclei. The central part of the fiber contains an abundance of mitochondrial enzymes and glycogen, but lacks myosin ATPase activity.
Type-1 muscle fiber hypotrophy is usually present. A variable degree of endomysial fibrosis and fatty replacement is present, often depending on time course and severity with more severe abnormalities increasing with age.
Internal nuclei (not necessarily centrally placed) are more common in patients with RYR1 mutations.[52]
Necklace fibers—fibers with internalized nuclei in a basophilic ring just below the sarcolemma—have been described in patients with MTM1 and DNM2 mutations.[53, 54]
Immunohistochemical studies have shown persistence of fetal vimentin and desmin and of neonatal myosin, giving further credence to the maturational arrest of muscle fibers.
Muscle fibers with central nuclei can also be seen in denervation, muscle fiber regeneration, and any chronic myopathy.
Congenital fiber-type disproportion (CFTD) has as the main pathologic hallmark small type-1 muscle fibers. The original definition requires that type-1 fibers are 12% smaller in diameter than type-2 fibers, although often the difference is closer to 50%. Other common features are type-1 fiber predominance and reduced or absent type-2B fibers.
This term was initially coined to describe a group of infants with small type-1 muscle fibers and the clinical syndrome of hypotonia and diffuse weakness that may improve with age. Other clinical features can include facial, bulbar, and respiratory weakness; short stature; low body weight; multiple joint contractures; scoliosis; long, thin face; and high arched palate. Ophthalmoplegia, cardiac disease, and intellectual disability are rare. Mutations in several genes can cause CFTD.
CFTD 1
Autosomal dominant mutations in ACTA1 are a rare cause of CFTD accounting for fewer than 10% of cases.[55] Mutations in the gene for α-actin are a common cause of nemaline myopathy. It has been shown that CFTD mutant α-actin is unable to properly interact with tropomyosin, leaving tropomyosin in the "switched off" position, thereby not allowing actin to interact with myosin. Furthermore, the sarcomeric disruption common in α-actin mutations that cause severe nemaline myopathy is not seen in patients with severe weakness due to CFTD. These data have lead to the hypothesis that the α-actin mutations that cause CFTD result in disturbed sarcomeric function rather than structure.[56]
Presentation is at birth with severe weakness most prominent in proximal, truncal, facial, and respiratory muscles. Severe feeding difficulties are present, and invasive ventilation is often needed. Most patients die due to progressive respiratory failure before 4 years of age.
CFTD 2
This is an X-linked recessive disease that has been described in patients with mutation in to two regions of the X chromosome, Xp22.13 to Xp11.4 and Xq13.1 to Xq22.1. From birth, these patients had marked ptosis, facial weakness, poor sucking, hypotonia, respiratory weakness, and relatively preserved limb strength. In one patient, there was a mild dilated cardiomyopathy that developed in infancy.[57]
CFTD 3
Autosomal recessive mutations in the gene for selenoprotein N are a rare cause of CFTD accounting for fewer than 10% of cases.[58] Mutations in the gene for selenoprotein N also cause multiminicore disease and congenital muscular dystrophy with rigid spine. The reason why different mutations cause different muscle pathologies is not clear, but clinical syndromes overlap with most patients having a rigid spine and respiratory insufficiency.[59] Patients with CFTD 3 will present before age 1 year with low tone and poor head control. There is noticable weakness in the neck and axial muscles. As the children grow older, a wheelchair may be needed. Respiratory insufficiency usually results in the need for nocturnal ventilation in the patient's 20s.
CFTD 4
The most common cause is due to autosomal dominant or sporadic (likely de novo autosomal dominant) mutations in the gene for α-tropomyosin 3 (TPM3). This subtype accounts for 25% of call cases of CFTD.[60] Mutations in TPM3 are a rare cause of nemaline myopathy, but they are a common cause of CFTD.[60] The reason why certain mutations cause rod formation while others cause CFTD is not known. Biopsy samples showed a predominance of type-1 fibers (83%) that were 72% smaller than type-2 fibers. Some mutations can cause CFTD in some family members and rod formation in others.
The onset of symptoms is usually before 1 year of age but may begin in young adulthood. Typically, hypotonia and delayed major motor milestones are early features, but independent ambulation is always achieved. Weakness of axial, proximal limb, facial, and ankle dorsiflexor muscles is common, as is ptosis, scapular winging, and a thin body habitus. Nearly all patients have respiratory insufficiency with nocturnal noninvasive ventilation needed in 50% of patients between the ages of 3 and 55 years.
CFTD 5
Autosomal dominant mutations in the gene for b-tropomyosin (TPM2) are a rare cause of CFTD.[61] Mutations in TPM2 more commonly cause rod myopathy. Interestingly, mutations in TPM2 and TPM3 can cause CFTD, nemaline rod myopathy, and cap myopathy suggesting that these may be related entities. Patients will present with neonatal hypotonia and delayed motor milestones as early features. Proximal, facial, and in severe cases, respiratory weakness is present.
RYR1-caused CFTD
Autosomal recessive mutations in the gene for RYR1 may be a common cause of CFTD, possibly up to 10% of cases.[62] All patients presented at birth with severe weakness and hypotonia with possible ophthalmoplegia except for one who presented at 2 years with difficulty running. The most severe cases developed progressive respiratory failure and died between 1 month and 3 years. Milder cases walked into their teens, although one patient at age 29 could only walk a few steps.
Although none of the patients with CFTD had a family history of malignant hyperthermia, standard precautions are prudent.[62]
Note that there are many other causes of type-1 fiber hypotrophy including other congenital myopathies (nemaline rod myopathy, centronuclear/myotubular myopathy, multiminicore myopathy), muscular dystrophies (eg, Emery-Dreifuss muscular dystrophy, LGMD2A, congenital muscular dystrophy with spine rigidity due to mutations in selenoprotein N), polymyositis, perinatal asphyxia, leukodystrophies, spinal muscular atrophy, arthrogryposis, and Pompe disease.
Mutations in the slow/β-cardiac myosin heavy-chain gene (MYH7) have been reported in sporadic or autosomal dominantly inherited cases. Mutations in MYH7 also cause Laing early adult-onset distal myopathy type 3 and cases of familial hypertrophic cardiomyopathy, dilated cardiomyopathy and left ventricular non-compaction. The same mutation may present with variable phenotypes as exemplified by one mutation (Leu1793Pro) shown to present with neonatal hypotonia, adult-onset proximal weakness and isolated neonatal cardiomyopathy.[63] Mutations in MYH7 also cause hypertrophic cardiomyopathy (CMH-1), dilated cardiomyopathy (CMD-1S), and familial left ventricular noncompaction.
Hyaline bodies are subsarcolemmal areas, mostly in type-1 muscle fibers, that are devoid of sarcomeres and react with myosin ATPase but not oxidative enzymes or glycogen. They are pink on hematoxylin and eosin (H&E) staining, and pale green with modified GT staining. They are composed of granular and filamentous material in continuity with adjacent thick myosin filaments. The hyaline bodies immunostain intensely with antibodies against the slow myosin heavy chain and have been proposed to result from myofibrillolysis of the mutated slow myosin heavy chain within type-1 muscle fibers.
Type-1 muscle fiber predominance is common.
Interestingly, some patients with a mutation in MYH7 do not have hyaline bodies on muscle biopsy sample.
Onset is usually in infancy or childhood but with variable penetrance; some patients present in adult life or may even be asymptomatic in their 40s.[64] Their weakness can be proximal, proximal and distal, or scapuloperoneal in distribution. Progression is minimal or very slow; more rapid progression is rare.
Sarcotubular myopathy
This myopathy is due to a mutation in Tripartite-motif containing gene 32 (TRIM32).
Inheritance is autosomal recessive, and all cases have the same mutation (D487N) that causes limb-girdle muscular dystrophy 2H (Manitoba Hutterite dystrophy).
TRIM 32 is an E3 ubiquitin ligase that is expressed in muscle. It interacts with myosin and can ubiquinate actin. E3 ubiquitin ligase activity is not abolished due to this mutation. Nevertheless, altered ability to ubiquinate may result in accumulation of proteins that are not tagged for degradation by the proteosomal system.[65]
EM reveals numerous small, membrane-bound vacuoles that appear to originate from the sarcotubular system and have reactivity to T-tubule and SR-associated proteins, most often affecting type-2 muscle fibers.
Inheritance is autosomal recessive. Onset occurs in childhood in most, but in mid-adult life in some, with mild-to-moderate proximal weakness and mild facial weakness. Other features include muscle atrophy, contractures, exercise-induced myalgias, and scapular winging. This disease is allelic with LGMD 2H (Limb-Girdle Muscular Dystrophy) making it likely that these two diseases are the same disorder.[66]
Reducing body myopathy
This is an X-linked dominant disease due to a mutation in Four and a half LIM domain 1 (FHL1).[67]
The LIM domain is a cysteine-rich double zinc-finger structure that bind zinc ions for protein stabilization. FHL proteins scaffold cytoskeletal and cell signaling complexes and help regulate gene transcription. FHL proteins are thought to be involved in myoblast migration and elongation as well as sarcomere formation through binding of myosin-binding protein C. In adult myofibers, FHL1 through the calcineurin signaling pathway helps to regulate myoblast fusion, skeletal muscle hypertrophy, and oxidative fiber-type shifting.
Cardiomyopathy is common in patients with FHL1 mutations and FHL1 plays multiple roles in the heart including modulation of conduction through interaction with the potassium channel KCNA5, regulation of cardiac hypertrophy through binding components of the MAPK signaling pathway and detection of mechanical stretch through interaction with the elastic N2B region of titin.
In most patients FHL1 levels are reduced suggesting that loss of normal protein function via reduced FHL1 protein expression of impairment of protein-partner binding may also be important in disease pathogenesis.
EM reveals numerous subsarcolemmal, non–membrane-bound aggregates composed of granulofilamentous and tubular structures, which stain pink with H&E and purple with the modified GT stain. The name "reducing body" was coined when the inclusions were found to have reducing activity when salts are applied to the muscle fiber.
Immunohistochemical analysis has shown features similar to that of aggresomes including perinuclear location and the presence of desmin, ubiquitin, and luminal endoplasmic reticulum chaperone GRP78. Wild-type and mutated FHL1 is also present in the inclusions and the aggregation of these (and other as yet unidentified) proteins may play a role in the pathogenesis of the disease through a toxic gain of function.
The clinical syndrome demonstrates overlapping features include progressive weakness, a rigid spine, scapular winging, and contractures. Cardiomyopathy and respiratory involvement are seen in most subtypes. However, there are also differences in age of onset, distribution, and severity of weakness and rate of progression.[67]
The most severe of the FHL1 myopathies is reducing body myopathy, named because of staining characteristics of intracytoplasmic aggregates. Age of onset varies from infancy to childhood and a few adult cases. In severe cases early-onset motor delay leads to progressive weakness with spine rigidity, early loss of ambulation, and death in infancy or childhood due to respiratory failure. Adult-onset cases present in the third or fourth decade of life with asymmetric proximal and scapuloperoneal weakness, which is slowly progressive. Cardiomyopathy is uncommon.[68]
Other subtypes, include:
X-linked dominant scapuloperoneal myopathy presents in the third or fourth decade of life with footdrop, proximal weakness, scapular winging, and cardiomyopathy. Rigid spine and contractures are late features. Men are affected earlier and more severely usually becoming wheelchair bound.[69]
X-linked myopathy with postural muscle atrophy presents in the third decade with scapulo-axial-peroneal weakness, atrophy of postural muscles, and bent/rigid spine. Hypertrophy of proximal upper limb muscles gives patients a pseudoathletic appearance.[70]
Emery-Dreifuss Muscular Dystrophy presentation is more fully described elsewhere. Typical features include cardiomyopathy and arrhythmia, progressive scapuloperoneal weakness, and contractures of the elbow, ankle, and spine.[71]
Rigid spine syndrome has been described in only one patient, a 13-year-old presenting with rigid spine, contractures, proximal weakness, scapular winging, and respiratory involvement. Cardiomyopathy was present.[72]
Why different mutations in FHL1 cause different syndromes is unknown, but mutations causing the more severe reducing body myopathy are often in exons 4/5, whereas mutations in the less severe Emery-Dreifuss muscular dystrophy are in exons 5–8.
Spheroid body myopathy
This myopathy is due to an autosomal dominant mutation in the gene for myotilin (titin immunoglobulin domain protein; TTID), which also causes LGMD type 1A and a myofibrillar myopathy. This has been described in one large kindred.[73]
Spheroid bodies are more common in type-1 muscle fibers and devoid of enzymatic activity. Electron microscopy shows fine filaments and streaming of Z disks. Immunohistochemical studies show the presence of desmin and ubiquitin, similar to what is found in many myofibrillar myopathies.
Myotilin binds actin and is thought to be involved in stabilization of actin bundles and anchorage of thin filaments at the Z disk.
This myopathy can be considered a myofibrillar myopathy/desminopathy since aggregates include desmin. Mutations in myotilin also cause LGMD type 1A (Limb-Girdle Muscular Dystrophy.
Presentation varied from childhood to the eighth decade, most often with proximal weakness that slowly progressed, as well as dysarthric speech.
Swallowing difficulties, loss of ambulation, and need for respiratory support occurred in a few individuals.
In the most recent edition of the textbook Myology (2004), the remaining congenital myopathies are divided into "probable," meaning several familial cases have been reported, and "possible or doubtful," meaning fewer than 10 cases have been reported.
Probable congenital myopathies
Fingerprint body myopathy: Patients present with hypotonia from infancy, proximal muscle weakness, and a delay in attaining motor milestones. Weakness progresses slowly or is nonprogressive. Additional features can include pectus excavatum and intellectual disability. Inheritance is likely autosomal recessive or sporadic. Small inclusions can be seen on H&E section in a subsarcolemmal distribution. On electron microscopy (EM), the fingerprint inclusions consist of nonmembrane-bound perinuclear collections of convoluted lamellae, most often in type-1 muscle fibers.
Cylindrical spirals myopathy: Onset occurs in late childhood to adulthood. Phenotypes are variable, and manifestations can include weakness (at times facioscapular), abnormal gait, myotonia, cramps, and scoliosis. Inheritance is autosomal dominant or sporadic. Light microscopy shows subsarcolemmal or intermyofibrillar clusters that stain blue on H&E, red-purple on modified GT stain, and negatively for myosin ATPase and SDH, most often in type-2 fibers. EM reveals the cylindrical spirals to appear as concentrically wrapped lamellae merging into tubular structures that resemble tubular aggregates.
Myopathy with tubular aggregates
These myopathies fall into the following 4 groups: (1) Childhood or adulthood onset of exercise-induced cramps, pain, and stiffness is the most common phenotype. Males are most commonly affected. Inheritance is sporadic, autosomal dominant, or autosomal recessive. (2) The onset occurs during childhood or adulthood and is a slowly progressive proximal weakness that may be accompanied by myalgias, cramps, or stiffness. Inheritance is sporadic, autosomal dominant, or autosomal recessive. (3) The onset occurs during infancy or childhood and includes myasthenic features of limb weakness and fatigability. Inheritance is autosomal recessive. (4) The onset occurs during late childhood and includes gyrate atrophy of the choroids and retina, resulting in progressive blindness. Inheritance is autosomal recessive and due to a deficiency in ornithine aminotransferase.
Tubular aggregates are collections of 50- to 80-nm tubules that originate in the SR. They are best visualized on NADH, where they stain a dark blue, as shown below.
View Image
Tubular aggregates, nicotinamide adenine dinucleotide (NADH) stain. Cytoplasmic collections of membranous tubules (derived from the sarcoplasmic retic....
They stain negatively with myosin ATPase and SDH. Aggregates are usually present in type 2 muscle fibers but also can be seen in type 1 fibers. They contain calsequestrin, heat shock proteins, SR ATPase, and SR calcium-pump proteins. Tubular aggregates also commonly occur in hypokalemic periodic paralysis and myotonia congenita, as well as less commonly in malignant hyperthermia, inflammatory myopathies, and alcoholic myopathy. Certain drugs, toxins, or hypoxia can also induce them. The tubular aggregates have been hypothesized to be an adaptive response to genetic or functional abnormalities affecting intracellular calcium flux, excitation-contraction coupling, or muscle fiber excitation.
Possible congenital myopathies
Myopathy with hexagonally cross-linked tubular arrays: Onset occurs during childhood or adulthood and includes slowly progressive, proximal weakness; fatigue; and exertional myalgia. Inheritance is unknown. EM reveals subsarcolemmal non–membrane-bound inclusions that, on cross-section, are arranged in a 6-spoked hexagonal pattern. The inclusions stain dark purple with modified GT stain and are found in only type-2 muscle fibers.
Trilaminar myopathy: Only one case has been reported with presentation at birth and was characterized by minimal movement, rigidity, and contractures. The course was nonprogressive. Light microscopy revealed a trilaminar appearance with 3 concentric zones when reacted with the modified GT or NADH stains. The inner and outer zones were densely stained, and the intermediate zone was unstained. On EM, the innermost zone had densely packed mitochondria, glycogen, electron-dense material, and filaments. The middle zone contained Z-disk streaming and well-organized myofibrils. The outermost zone contained cytoplasm with rare mitochondria, filaments, vesicles, and lipids.
Zebra body myopathy: Only two congenital-onset cases have been reported and were characterized by hypotonia and weakness that progressed slowly or was nonprogressive. On EM, zebra bodies are characterized by Z-band material connected by fine filaments in a pseudosarcomeric pattern, resulting in a striped appearance. Zebra bodies are normally present in myotendinous junctions, intrafusal fibers, extrafusal fibers, extraocular muscle, and cardiac muscle. Their function is unknown.
Congenital myopathy with mosaic fibers and interlacing sarcomeres: Only 1 case with childhood onset, which was characterized by proximal weakness, scoliosis, and talipes equinovarus, has been reported. Progression was minimal, but cardiomyopathy and respiratory insufficiency developed in adulthood. Light microscopy revealed a mosaic pattern of light and dark staining on myosin ATPase. EM revealed bands of myofibrils at right angles to other myofibrils, resulting in an interlacing appearance.
Congenital myopathy with apoptotic changes: Only 1 case has been reported and was characterized by congenital-onset hypotonia, proximal weakness, and severe mental retardation. Light microscopy and EM revealed chromatin condensation and nuclear fragmentation. Some fibers were positive for Bax, caspase-3, or TUNNEL.
Broad A-band disease: Two sporadic cases have been described with congenital-onset hypotonia and mild nonprogressive proximal muscle weakness. EM revealed disorganization of the thick filaments, leading to a loss of distinct A-band/I-band demarcation and the appearance of smearing or broadening of the A-band.
Lamellar body myopathy: Only one case has been described and was characterized by congenital onset, weakness with progression to respiratory failure, and death at age 5 years. Light microscopy revealed increased connective tissue surrounding muscle fibers that stained positively for laminin and fibronectin. EM revealed that these areas contained concentric lamellar bodies between the 2 layers of basement membrane.
Myopathy with muscle spindle excess: Only one case has been described and was characterized by congenital onset, hypotonia, proximal weakness, and arthrogryposis. Cardiomyopathy and respiratory failure led to death at about age 1 year. Light microscopy revealed an excess of muscle fiber clusters within fibrous capsules consistent with muscle spindles.
In the evaluation of a patient with possible congenital myopathy, consideration of the pattern of clinical phenotype, laboratory examination, and electrodiagnostic studies are the first line of evaluations to ensure that patients clinically fit.
However, phenotypic correlation with a genetically congruent mutations is the gold standard for diagnosis. At times, however, a definitive gene is not able to be identified. In these cases, returning to muscle biopsy findings can help confirm the diagnosis based upon the known histopathologic features.
Initially, as with any child or person with weakness, localization by history and examination to a peripheral cause is prudent. Subsequently, biochemical evaluation with a creatine kinase can rapidly help narrow the differential. Significantly elelvated creatine kinase levels (>5 times the upper range of normal) is unlikely to be a congenital myopathy and other diseases such as the muscular dystrophies should be considered. However, in infants, be catious that early testing after birth (within a few days to a week) can demonstrate a falsely elevated level from baseline and may need to be rechecked.
Subsequently, electrodiagnostic evaluation can be helpful in determining neurogenci from myopathic disease in an infant and further narrow the differential. This allows the provider to proceed with genetic testing and/or muscle biopsy for further evaluation.
In previously diagnosed patients, a multidisciplinary approach is warranted given the complex care of these patients.
Creatine kinase (CK) level is typically either normal or mildly elevated (2–5 times the normal range) in all of the congenital myopathies. There is some suggestion that more moderately elevated levels can be seen in central core disease as well as asymptomatic carriers of the ryanodine receptor mutation in CCD.
If the CK level is very high (>5 times the upper limit of normal), this is suggestive of a muscular dystrophy.
Electromyography (EMG) and nerve conduction studies (NCS)
These studies test the electrical patterns of muscles and nerves. They can help to confirm the diagnosis, but results from these tests can be normal in a patient with congenital myopathy.
The greatest value of EMG/NCS is to help exclude other causes of congenital myopathy. As such, these tests should be considered prior to a more costly, and invasive, muscle biopsy or focused genetic testing. EMG/NCS should be considered in all cases of congenital myopathy given that creatine kinase level is not typically suggestive of a muscle disease given its typically normal range of values.
In congenital myopathy, NCS findings can be normal or demonstrate low-amplitude responses in the motor nerve conduction studies in severe cases, while the EMG findings are either normal or show the typical small-amplitude, narrow-duration motor unit potentials (MUPs) that are seen in myopathies. Fibrillations and positive sharp waves are rare except in the more severe phenotypes.
Electrocardiography (ECG) and echocardiogram
Cardiac disease may be prominent in nemaline myopathy or, at times, in other congenital myopathies. Obtain an ECG when considering these diagnoses. Unless there are clinical symptoms, this testing is typically done after genetic or pathologic confirmation.
Pulmonary function studies/sleep studies
With the common respiratory weakness, evaluation for pulmonary function in appropriately aged patients is often warranted. The relationship to skeletal muscle weakness and respiratory weakness varies by the underlying disorder. As such, one should use symptology and genotype rather than muscle strength to direct when to obtain testing. Additionally, nocturnal hypoventilation often preceeds daytime symptoms but can be missed in a clinical encounter without directed questioning of patients.
The utility of muscle biopsy has changed significantly over the past few decades. While traditionally the muscle biopsy would be an early step, and conducted prior to genetic testing, this trend is changing. With the cheaper, more rapid turnaround of genetic testing, looking to genotyping patients as first-line evaluations in patients who are not critically ill can be considered.
In critically ill neonates, a muscle biopsy may provide a category of disease as well as give some indication of severity based upon histopathologic features. However, genetic identification remains the ideal standard to allow for further counseling.
The biopsy should be conducted in a muscle that is weak but that retains bulk and some strength. Typically, the vastus lateralis remains an ideal muscle of choice. The evaluation should be undertaken at a facility skilled with both procuring, processing, and evaluating muscle biopsies given technical aspects can limit interpretation. Additionally, availability of muscle-specific testing and electron microspcopy can be helpful in diagnosis.
Finally, in infants and neonates who have mild symptoms, an early biopsy may be normal and need to be repeated years later after the pathologic features have been able to develop.
Currently, there is no genetic cure for any congenital myopathy. As such, treatment remains focused on symptomatic treatment from therapy, medical, surgical, and psychologic perspectives.
The focus on treatment of the congenital myopathies is to evaluate and slow the progression of symptoms while maintaining activities of daily living.
Muscle treatment
The treatment of muscle weakness revolves around stretching, bracing, and supportive care. Contractures can severely limit activities of daily living. Given this, involvement of physical therapy for both stretching and appropriate bracing is needed. However, depending upon the pathophysiology of the disease, bracing is sometimes contraindicated as imobility can result in worsening weakness. In some cases, where the weakness is severe enough, there may be a need for assistive devices including wheelchairs or similar mobility devices.
Pulmonary treatment
Each congenital myopathy can have a varied degree of respiratory involvement secondary to the pulmonary components of the disease; being aware of signs is relevant. Neuromuscular weakness is often more prevelant during sleep. As such, evaluation of signs of hypoventilation at night, including morning headaches, snoring, or daytime sleepiness, should be undertaken. In infants, respiratory support for frequent or prolonged respiratory illnesses may be needed.
Based upon the subtype, the degree of limb weakness does not always correlate to the severity of respiratory weakness. As such, when respiratory involvement is suspected, it may be helpful to consult a pulmonologist and perform pulmonary function tests (if appropriate for the patient's age). Commonly, patients will have a restrictive pattern of lung disease.
Cardiac treatment
In cases of known genes with cardiac involvement, cardiac care based on subtype should be followed. This may involve pre-symptomatic screening to evaluate the need for early interventions.
Orthopedic treatment
Skeletal abnormalities are frequent complications of patients with a congenital myopathy. As such, contracture prevention, as noted above, should be considered. The development of scoliosis or kyphosis may impede standing, sitting, walking, and respiratory function. Treatment options include bracing or surgical correction with spinal fusion. Timing of scoliosis correction is important given the possible underlying respiratory weakness.
Surgery for treatment of contractures, foot deformities, and scolioisis is most common.
Gastroinestinal system
A gastrostomy tube is sometimes needed for newborns with feeding difficulties. However, given the trend for many babies to improve over months to a few years, this is not necessarily a permanent issue.
Pulmonary system
As with the gastrointestinal system, infants can require tracheostomy early on after birth for airway protection. However, they may be able to be decannulated after months to years due to improvements. This course is dictated by the subtype of disease.
Treatment of congenital myopathies, at any age, requires a multidisciplinary team. Typically, the neuromuscular physician will lead the team with other consultants based upon the patient's needs. The other team members may include:
Orthopedic surgeon
Pulmonologist
Cardiologist
Gastroenterologist/dietician
Geneticist/genetic counselor
Physiatrist
Physical/occupational/speech therapists
Orthotist
Palliative care physician
Muscular Dystrophy Association or advocacy organization member
While no dietary restrictions are indicated in the myopathies, diet should be tailored to the caloric needs of the patient. This may include restricting calories, especially in children with minimal mobility to avoid overwhelming weight gain.
Weight may not follow the growth curve or may be low given a lack of muscle mass.
Activity level is based upon the combination of muscle weakness, respiratory concerns, and orthopedic restrictions. However, one of the main goals is to have continued functional ability.
For children, regular school attendance should be encouraged with modified educational plans for their needs. As able, patients can participate in regular physical activity.
Follow-up and outpatient care depends on disease severity. In children, or a newly diagnosed patient, more frequent visits, such as every 3–6 months, can be considered. For older patients or those with milder disease, at least yearly visits are warranted.
At each visit care should be directed based on the exact needs of the patient but should also involve assessments of the following:
Muscle function
Contractures
Ability to perform activities of daily living
Cardiopulmonary function
For patients requiring more than one provider, consider a multidisciplinary approach.
Inpatient care is directed at specific needs. Often infants or neonates will have a longer inpatient stay after birth. Additionally, given the weak respiratory muscles, admission may be warranted as needed.
In patients with neuromuscular weakness the method of supportive care and methods of extubating differ from patients without muscle weakness. This often presents as different supportive settings, more frequent interventions by the respiratory therapist, and, in some cases, extubating the patient to non-invasive support regardless of how well they were doing on the ventilator. As such, consultation with a pulmonologist or critical care specialist who is experienced in caring for patients with neuromuscular disease is often warranted.
While ill, there are certain medications that should be avoided due to their muscle relaxant properties. While not an absolute contraindication, a patient;s underlying muscle weakness has the potential to significantly worsen when exposed to these medications.
Patients with central core disease (CCD) (less frequently with multicore disease) are inclined to develop malignant hyperthermia. However, since the precise diagnosis may not be known, precautions should be taken in all patients with a presumed diagnosis of congenital myopathy. General anesthesia usually triggers a full-blown episode, but excessive heat, neuroleptic drugs, alcohol, or infections may trigger milder episodes.
If surgery is required, these patients (and their relatives) should avoid inhaled anesthetics (except nitrous oxide) and succinylcholine.
Signs and symptoms of malignant hyperthermia include the following:
Elevated pCO2
Muscle rigidity
Tachycardia
Hemodynamic instability
Hyperventilation
Cyanosis
Lactic acidosis
Fever
Hyperkalemia
Hypercalcemia
Myoglobinuria
Death may result from pulmonary edema, coagulopathy, ventricular fibrillation, cerebral edema, or renal failure
Appropriate treatment includes the following:
Stopping inhalational anesthetics or succinylcholine
Hyperventilating the patient with 100% oxygen
Administering dantrolene up to 10 mg/kg
Providing bicarbonate for metabolic acidosis
Cooling the patient
Monitoring for arrhythmias and hyperkalemia
Maintaining urine output over 2 mL/kg/h
Avoiding calcium antagonists and beta-blockers
Monitoring in an ICU for 24–48 hours
Cardiac involvement can occur in patients with congenital myopathies, especially nemaline myopathy, CCD, and multiminicore disease.
Pulmonary insufficiency can occur in any form of congenital myopathy that presents with severe neonatal hypotonia. It is more common or more severe in nemaline myopathy, X-linked and autosomal myotubular/centronuclear myopathy, multiminicore disease, and reducing body myopathy. This is especially important to assess before surgery since postoperative respiratory failure can occur.
Skeletal deformities, including contractures and scoliosis, are common in patients with most of the congenital myopathies.
Obstetric complications during childbirth are uncommon in mothers with congenital myopathy. However, neonatal complications can include polyhydramnios; decreased fetal movements; or complications related to fetal distress, abnormal presentation, failure to progress, or prematurity.
Genetic counseling is often helpful to assist patients with family-planning decisions. However, definitive prenatal diagnosis is only possible if a disease-causing mutation has been identified. Genetic counseling is especially important for families of patients with CCD to avoid unexpected cases of malignant hyperthermia in asymptomatic relatives.
What are congenital myopathies?What is the pathophysiology of congenital myopathies?What is the prevalence of congenital myopathies?What is the mortality and morbidity associated with congenital myopathies?What are the sexual predilections of congenital myopathies?At what age are congenital myopathies typically diagnosed?What is the prognosis of congenital myopathies?Which clinical history findings are characteristic of congenital myopathies?What is nemaline myopathy (NEM)?What causes nemaline myopathy 1 (NEM1)?What causes nemaline myopathy 2 (NEM2)?What causes nemaline myopathy 3 (NEM3)?What causes nemaline myopathy 4 (NEM4)?What causes nemaline myopathy 5 (NEM5)?What causes nemaline myopathy 6 (NEM6)?What causes nemaline myopathy 7 (NEM7)?What causes nemaline myopathy 8 (NEM8)?What causes nemaline myopathy 9 (NEM9)?What causes nemaline myopathy 10 (NEM10)?What are the pathologic findings characteristic of nemaline myopathy (NEM)?What causes central core disease (CCD)?What causes malignant hyperthermia?What are the signs and symptoms hyperCKemia?What causes multiminicore disease?What are the centronuclear myopathies (CNMs)?What causes centronuclear myopathy 1 (CNM1)?What causes centronuclear myopathy 3 (CNM3)?What causes centronuclear myopathy 4 (CNM4)?What causes centronuclear myopathy 2 (CNM2)?What causes centronuclear CNM5, CNM6 and CMN (RYR1)?What is the role of titin in the etiology of centronuclear myopathies (CNMs)?What causes centronuclear myopathy X (CNMX)?Which pathologic findings are characteristic of centronuclear myopathies (CNMs)?What causes congenital fiber-type disproportion 1 (CFTD1)?What is the role of RYR1 in the etiology of congenital fiber-type disproportion (CFTD)?What is congenital fiber-type disproportion (CFTD)?What causes congenital fiber-type disproportion 2 (CFTD2)?What causes congenital fiber-type disproportion 3 (CFTD3)?What causes congenital fiber-type disproportion 4 (CFTD4)?What causes congenital fiber-type disproportion 5 (CFTD5)?What causes myosin storage myopathy (hyaline body myopathy)?What causes sarcotubular myopathy?What is the role of FHL1 mutations in the etiology of congenital myopathies?What causes spheroid body myopathy?What is the difference between probable and possible congenital myopathies?What are the probable congenital myopathies?What are possible congenital myopathies?What are the differential diagnoses for Congenital Myopathies?How are congenital myopathies diagnosed?What is the role of lab testing in the workup of congenital myopathies?What is the role of EMG in the workup of congenital myopathies?What is the role of ECG in the workup of congenital myopathies?What is the role of pulmonary function testing (PFT) and sleep studies in the workup of congenital myopathies?What is the role of biopsy in the workup of congenital myopathies?What is the role of imaging studies in the workup of congenital myopathies?How are congenital myopathies treated?What is the focus of treatment for congenital myopathies?How is muscle weakness treated in congenital myopathy?How is respiratory weakness treated in congenital myopathy?How is cardiac care selected for patients with congenital myopathies?How are skeletal abnormalities treated in patients with congenital myopathies?What is the role of orthopedic surgery in the treatment of congenital myopathies?When is a gastrostomy tube indicated in the treatment of congenital myopathies?When is tracheostomy indicated in the treatment of congenital myopathies?Which specialist consultations are beneficial to patients with congenital myopathies?Which dietary modifications are used in the treatment of congenital myopathies?Which activity modifications are used in the treatment of congenital myopathies?What is included in the long-term monitoring of congenital myopathies?When is inpatient care indicated for the treatment of congenital myopathies?How is malignant hyperthermia diagnosed and treated in patients with a congenital myopathy?What are the possible complications of congenital myopathies?What is included in patient education about congenital myopathies?
Matthew Harmelink, MD, Assistant Professor of Neurology, Division of Child Neurology, Department of Neurology, Medical College of Wisconsin; Director of Pediatric Neuromuscular Program, Division of Pediatric Neurology, Children's Hospital of Wisconsin
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Three Gaits, Inc (Non-profit therapeutic riding stable)<br/>Serve(d) as a speaker or a member of a speakers bureau for: Biogen<br/>Received research grant from: CureSMA<br/>Received income in an amount equal to or greater than $250 from: Biogen (Consultant, Advisory Board); Avexis (Advisory Board); PTC (Advisory Board); Sarepta (Advisory Board); Connected Research & Consulting (Consulting); Optio Biopharma Solutions, LLC (Consulting).
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Kenneth J Mack, MD, PhD, Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic
Disclosure: Nothing to disclose.
Chief Editor
Amy Kao, MD, Attending Neurologist, Children's National Medical Center
Disclosure: Have stock (managed by a financial services company) in healthcare companies including Allergan, Cellectar Biosciences, CVS Health, Danaher Corp, Johnson & Johnson.
Additional Contributors
Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital
Disclosure: Nothing to disclose.
Robert J Baumann, MD, Professor of Neurology and Pediatrics, Department of Neurology, University of Kentucky College of Medicine
Klein A, Jungblath H, Clement E, Lillis S, Abbs S, Munot P, et al. Muscle Magnetic Resonance Imaging in Congenital Myopathies due to Ryanodine Receptor Type 1 Gene Mutations. Arch Neurol. Sep 2011. 68:1171-1179.
Nemaline rod myopathy, Gomori trichrome (GT) stain. Dark blue structures are seen only with this stain. They contain Z disk material, including alpha-actinin and tropomyosin.
Tubular aggregates, nicotinamide adenine dinucleotide (NADH) stain. Cytoplasmic collections of membranous tubules (derived from the sarcoplasmic reticulum) can be present in various myopathies, including myopathy with tubular aggregates, hypokalemic periodic paralysis, malignant hyperthermia, myotonia congenita, and ceratin toxic myopathies.
Central core disease, nicotinamide adenine dinucleotide (NADH) stain. In the central core, mitochondria and oxidative enzymes are absent. Cores are also present on cytochrome oxidase and succinate dehydrogenase (SDH) stains.
Nemaline rod myopathy, Gomori trichrome (GT) stain. Dark blue structures are seen only with this stain. They contain Z disk material, including alpha-actinin and tropomyosin.
Centronuclear myopathy, hematoxylin and eosin stain. Note the numerous, centrally placed nuclei. Normal nuclei are at the periphery of the muscle fiber.
Tubular aggregates, nicotinamide adenine dinucleotide (NADH) stain. Cytoplasmic collections of membranous tubules (derived from the sarcoplasmic reticulum) can be present in various myopathies, including myopathy with tubular aggregates, hypokalemic periodic paralysis, malignant hyperthermia, myotonia congenita, and ceratin toxic myopathies.
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